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71.
Most proteins that participate in cellular signalling networks contain modular protein-interaction domains. Multiple versions of such domains are present within a given organism: the yeast proteome, for example, contains 27 different Src homology 3 (SH3) domains. This raises the potential problem of cross-reaction. It is generally thought that isolated domain-ligand pairs lack sufficient information to encode biologically unique interactions, and that specificity is instead encoded by the context in which the interaction pairs are presented. Here we show that an isolated peptide ligand from the yeast protein Pbs2 recognizes its biological partner, the SH3 domain from Sho1, with near-absolute specificity--no other SH3 domain present in the yeast genome cross-reacts with the Pbs2 peptide, in vivo or in vitro. Such high specificity, however, is not observed in a set of non-yeast SH3 domains, and Pbs2 motif variants that cross-react with other SH3 domains confer a fitness defect, indicating that the Pbs2 motif might have been optimized to minimize interaction with competing domains specifically found in yeast. System-wide negative selection is a subtle but powerful evolutionary mechanism to optimize specificity within an interaction network composed of overlapping recognition elements. 相似文献
72.
Modelling vaccination strategies against foot-and-mouth disease 总被引:1,自引:0,他引:1
Vaccination has proved a powerful defence against a range of infectious diseases of humans and animals. However, its potential to control major epidemics of foot-and-mouth disease (FMD) in livestock is contentious. Using an individual farm-based model, we consider either national prophylactic vaccination campaigns in advance of an outbreak, or combinations of reactive vaccination and culling strategies during an epidemic. Consistent with standard epidemiological theory, mass prophylactic vaccination could reduce greatly the potential for a major epidemic, while the targeting of high-risk farms increases efficiency. Given sufficient resources and preparation, a combination of reactive vaccination and culling might control ongoing epidemics. We also explore a reactive strategy, 'predictive' vaccination, which targets key spatial transmission loci and can reduce markedly the long tail that characterizes many FMD epidemics. These analyses have broader implications for the control of human and livestock infectious diseases in heterogeneous spatial landscapes. 相似文献
73.
Thomas JW Touchman JW Blakesley RW Bouffard GG Beckstrom-Sternberg SM Margulies EH Blanchette M Siepel AC Thomas PJ McDowell JC Maskeri B Hansen NF Schwartz MS Weber RJ Kent WJ Karolchik D Bruen TC Bevan R Cutler DJ Schwartz S Elnitski L Idol JR Prasad AB Lee-Lin SQ Maduro VV Summers TJ Portnoy ME Dietrich NL Akhter N Ayele K Benjamin B Cariaga K Brinkley CP Brooks SY Granite S Guan X Gupta J Haghighi P Ho SL Huang MC Karlins E Laric PL Legaspi R Lim MJ Maduro QL Masiello CA Mastrian SD 《Nature》2003,424(6950):788-793
The systematic comparison of genomic sequences from different organisms represents a central focus of contemporary genome analysis. Comparative analyses of vertebrate sequences can identify coding and conserved non-coding regions, including regulatory elements, and provide insight into the forces that have rendered modern-day genomes. As a complement to whole-genome sequencing efforts, we are sequencing and comparing targeted genomic regions in multiple, evolutionarily diverse vertebrates. Here we report the generation and analysis of over 12 megabases (Mb) of sequence from 12 species, all derived from the genomic region orthologous to a segment of about 1.8 Mb on human chromosome 7 containing ten genes, including the gene mutated in cystic fibrosis. These sequences show conservation reflecting both functional constraints and the neutral mutational events that shaped this genomic region. In particular, we identify substantial numbers of conserved non-coding segments beyond those previously identified experimentally, most of which are not detectable by pair-wise sequence comparisons alone. Analysis of transposable element insertions highlights the variation in genome dynamics among these species and confirms the placement of rodents as a sister group to the primates. 相似文献
74.
对称矩阵空间上秩1非增长的加法映射 总被引:1,自引:1,他引:0
Ming-Huat Lim 《黑龙江大学自然科学学报》2004,21(4):35-36
刻划了特征不为2及3的域上所有从一个第二对称积空间到另一个的保形如λu·u(u是向量且λ是纯量)的可分解元素的加法映射. 相似文献
75.
Body weight, diet and home range area in primates. 总被引:10,自引:0,他引:10
Primates show a strong positive relationship between body weight and home range area. Dietary habits also influence home range area. Folivorous primates occupy smaller home range areas for their body weight than do frugivores and omnivores. Primates generally require smaller home range area per individual than solitary terrestrial mammals, but primates living in social groups have much larger total home range than individual solitary mammals. This trend may necessitate higher expenditures of energy in food-gathering or modifications in movement patterns. 相似文献
76.
Yeon Ju Kim Jangho Kim Chunjie Tian Hye Jin Lim Young Sun Kim Jong Hoon Chung Yun-Hoon Choung 《Cellular and molecular life sciences : CMLS》2014,71(19):3859-3871
Cis-diamminedichloroplatinum (cisplatin) is an effective chemotherapeutic drug for cancer therapy. However, most patients treated with cisplatin are at a high risk of ototoxicity, which causes severe hearing loss. Inspired by the “Good Samaritan effect” or “bystander effect” from gap junction coupling, we investigated the role of gap junctions in cisplatin-induced ototoxicity as a potential therapeutic method. We showed that connexin 43 (Cx43) was highly expressed in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, mediating cell–cell communication. The viability of HEI-OC1 cells was greatly decreased by cisplatin treatment, and cisplatin-treated HEI-OC1 cells showed lower Cx43 expression compared to that of untreated HEI-OC1 cells. In particular, high accumulation of Cx43 was observed around the nucleus of cisplatin-treated cells, whereas scattered punctuate expression of Cx43 was observed in the cytoplasm and membrane in normal cells, suggesting that cisplatin may interrupt the normal gap junction communication by inhibiting the trafficking of Cx43 to cell membranes in HEI-OC1 cells. Interestingly, we found that the inhibition of gap junction activity reduced cisplatin-induced apoptosis of auditory hair cells. Cx43 siRNA- or 18α-GA-treated HEI-OC1 cells showed higher cell viability compared to control HEI-OC1 cells during cisplatin treatment; this was also supported by fluorescence recovery after photobleaching studies. Inhibition of gap junction activity reduced recovery of calcein acetoxymethyl ester fluorescence compared to control cells. Additionally, analysis of the mechanisms involved demonstrated that highly activate extracellular signal-regulated kinase and protein kinase B, combined with inhibition of gap junctions may promote cell viability during cisplatin treatment. 相似文献
77.
The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells 总被引:45,自引:0,他引:45
78.
Y Okada X Sim MJ Go JY Wu D Gu F Takeuchi A Takahashi S Maeda T Tsunoda P Chen SC Lim TY Wong J Liu TL Young T Aung M Seielstad YY Teo YJ Kim JY Lee BG Han D Kang CH Chen FJ Tsai LC Chang SJ Fann H Mei DC Rao JE Hixson S Chen T Katsuya M Isono T Ogihara JC Chambers W Zhang JS Kooner;KidneyGen Consortium;CKDGen Consortium E Albrecht;GUGC consortium K Yamamoto M Kubo Y Nakamura N Kamatani N Kato J He YT Chen YS Cho ES Tai T Tanaka 《Nature genetics》2012,44(8):904-909
Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ~110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function. 相似文献
79.
Manning AK Hivert MF Scott RA Grimsby JL Bouatia-Naji N Chen H Rybin D Liu CT Bielak LF Prokopenko I Amin N Barnes D Cadby G Hottenga JJ Ingelsson E Jackson AU Johnson T Kanoni S Ladenvall C Lagou V Lahti J Lecoeur C Liu Y Martinez-Larrad MT Montasser ME Navarro P Perry JR Rasmussen-Torvik LJ Salo P Sattar N Shungin D Strawbridge RJ Tanaka T van Duijn CM An P de Andrade M Andrews JS Aspelund T Atalay M Aulchenko Y Balkau B Bandinelli S Beckmann JS Beilby JP Bellis C Bergman RN Blangero J 《Nature genetics》2012,44(6):659-669
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. 相似文献
80.
Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis 总被引:1,自引:0,他引:1
Franke A Balschun T Karlsen TH Hedderich J May S Lu T Schuldt D Nikolaus S Rosenstiel P Krawczak M Schreiber S 《Nature genetics》2008,40(6):713-715
Following up on recent genome-wide association studies (GWAS) of Crohn's disease, we investigated 50 previously reported susceptibility loci in a German sample of individuals with Crohn's disease (n = 1,850) or ulcerative colitis (n = 1,103) and healthy controls (n = 1,817). Among these loci, we identified variants in 3p21.31, NKX2-3 and CCNY as susceptibility factors for both diseases, whereas variants in PTPN2, HERC2 and STAT3 were associated only with ulcerative colitis in our sample collection. 相似文献